The invention relates to the subject matter referred to in the claims, i.e. homoglutamic acid derivatives of the general formulas I and/or II, their precursors of the formula III, their use and their preparation processes.
The early diagnosis of malignant tumour diseases plays an important role in the survival prognosis of a tumour patient. For this diagnosis, non-invasive diagnostic imaging methods are an important aid. In the last years, in particular the PET (Positron Emission Tomography) technology has been found to be particularly useful. The sensitivity and specificity of the PET technology depends essentially on the signal-giving substance (tracer) used and on its distribution in the body. In the hunt for suitable tracers, one tries to make use of certain properties of tumours which differentiate tumour tissue from healthy surrounding tissue. The preferred commercial isotope used for PET applications is 18F. Owing to the short half-life of less than 2 hours, 18F is particularly demanding when it comes to the preparation of suitable tracers. This isotope does not allow for complicated long synthesis routes and purification procedures, since otherwise a considerable amount of the radioactivity of the isotope will already have faded away before the tracer can be used for diagnosis. Accordingly, it is frequently not possible to apply established synthesis routes for non-radioactive fluorinations to the synthesis of 18F tracers. Furthermore, the high specific activity of 18F (about 80 GBq/nmol) leads to very low substance amounts of [18F]-fluoride for the tracer synthesis, which in turn requires an extreme excess of precursor, making the result of a radio synthesis strategy based on a non-radioactive fluorination reaction unpredictable.
FDG ([18F]-2-Fluorodeoxyglucose)-PET is a widely accepted and frequently used auxiliary in the diagnosis and further clinical monitoring of tumour disorders. Malignant tumours compete with the host organism for glucose as nutrient supply (Warburg O., Über den Stoffwechsel der Carcinomzelle [The metabolism of the carcinoma cell], Biochem. Zeitschrift 1924; 152: 309-339; Kellof G., Progress and Promise of FDG-PET Imaging for Cancer Patient Management and Oncologic Drug Development, Clin. Cancer Res. 2005; 11(8): 2785-2807).
Compared to the surrounding cells of the normal tissue, tumour cells usually have an increased glucose metabolism. This is exploited when using fluorodeoxyglucose (FDG), a glucose derivative which is increasingly transported into the cells, where, however, it is metabolically captured as FDG 6-phosphate after phosphorylation (“Warburg effect”). Accordingly, 18F-labelled FDG is an effective tracer for detecting tumour disorders in patients using the PET technology. In the hunt for novel PET tracers, recently, amino acids have been employed increasingly for 18F PET imaging (for example (review): Eur. J. Nucl. Med. Mol. Imaging May 2002; 29(5): 681-90). Here, some of the 18F-labelled amino acids are suitable for measuring the rate of protein synthesis, but most other derivatives are suitable for measuring the direct cellular uptake in the tumour. Known 18F-labelled amino acids are derived, for example, from tyrosine amino acids, phenylalanine amino acids, proline amino acids, asparagine amino acids and unnatural amino acids (for example J. Nucl. Med. 1991; 32: 1338-1346, J. Nucl. Med. 1996; 37: 320-325, J. Nucl. Med. 2001; 42: 752-754 and J. Nucl. Med. 1999; 40: 331-338). 18F-labelled homoglutamic acid derivatives are not known up to date.
The PET tracers currently used in tumour diagnosis have some undisputed disadvantages: thus, FDG is preferably accumulated in cells having an elevated glucose metabolism; however, under different pathological and physiological conditions, as also in elevated glucose metabolism in the cells and tissues involved, for example infection sites or wound healing (summarized in J. Nucl. Med. Technol. (2005), 33, 145-155). Frequently, it is still difficult to ascertain whether a lesion detected via FDG-PET is really of neoplastic origin or is the result of other physiological or pathological conditions of the tissue. Overall, the diagnosis by FDG-PET in oncology has a sensitivity of 84% and a specificity of 88% (Gambhir et al., “A tabulated summary of the FDG PET literature”, J. Nucl. Med. 2001, 42, 1-93S). The imaging of brain tumours, for example, is very difficult owing to the high accumulation of FDG in healthy brain tissue.
In some cases, the 18F-labelled amino acid derivatives currently known are well suited for the detection of tumours in the brain ((review): Eur. J. Nucl. Med. Mol. Imaging. 2002 May; 29(5): 681-90); however, in the case of other tumours, they are not able to compete with the imaging properties of the “Goldstandard” [18F]2-FDG. The metabolic accumulation and retention of the current F-18-labelled amino acids in tumour tissue is generally lower than of FDG. In addition, the preparation of isomerically pure F-18-labelled non-aromatic amino acids is chemically very demanding.
Similarly to glucose, for glutamic acid and glutamine, too, an increased metabolism in proliferating tumour cells has been described (Medina, J. Nutr. 1131: 2539S-2542S, 2001; Souba, Ann Surg 218: 715-728, 1993). The increased rate of protein and nucleic acid syntheses and the energy generation per se are thought to be the reasons for an increased glutamine consumption of tumour cells. The synthesis of corresponding C-11- and C-14-labelled compounds, which are thus identical to the natural substrate, has already been described in the literature (for example Antoni, Enzyme Catalyzed Synthesis of L-[4-C-11]aspartate and L-[5-C-11]glutamate. J. Labelled Compd. Radiopharm. 44; (4) 2001: 287-294 and Buchanan, The biosynthesis of showdomycin: studies with stable isotopes and the determination of principal precursors, J. Chem. Soc. Chem. Commun.; EN; 22; 1984; 1515-1517). First tests with the C-11-labelled compound indicate no significant accumulation in tumours.
It is an object of the present invention to provide novel compounds which, in [18F]-labelled form, are suitable for PET-based diagnosis.